A Flexible Strategy for Modular Synthesis of Curcuminoid‐BF<sub>2</sub>/Curcuminoid Pairs and Their Comparative Antiproliferative Activity in Human Cancer Cell Lines

Abonı́a, Rodrigo; Laali, Kenneth K.; Somu, Dawn Raja; Bunge, Scott D.; Wang, Esther C.

doi:10.1002/cmdc.201900640

Cited by 9 publications

(6 citation statements)

References 30 publications

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“…By using a different strategy (Scheme 2) a library of bis-NSAID/CUR and mono-NSAID/CUR conjugates were synthesized, from which the corresponding CUR-BF 2 adducts were obtained by reaction with BF 3 . [25] Collectively these efforts led to the synthesis and isolation of libraries of hybrid compounds shown in Figures 1-2. Octanol/water partition coefficients (LogP) are displayed below each structure.…”

Section: Resultsmentioning

confidence: 99%

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Curcumin Conjugates of Non‐steroidal Anti‐Inflammatory Drugs: Synthesis, Structures, Anti‐proliferative Assays, Computational Docking, and Inflammatory Response

et al. 2020

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In an effort to combine the anti‐proliferative effect of CUR‐BF2 and CUR compounds with anti‐inflammatory benefits of non‐steroidal anti‐inflammatory drugs (NSAIDs), a library of the bis‐ and mono‐NSAID/CUR‐BF2 and NSAID/CUR conjugates were synthesized by coupling flufenamic acid, flurbiprofen, naproxen, indomethacin, and ibuprofen to diversely substituted hydroxy‐benzaldehydes via an ester linkage, and by subsequent reaction with acetylacetone‐BF2 to form the bis‐ and the mono‐NSAID/CUR‐BF2 adducts. Since conversion to NSAID/CUR by the previously developed decomplexation protocol showed limited success, a set of NSAID/CUR conjugates were independently prepared by directly coupling the NSAIDs with parent curcumin. The bis‐NSAID/CUR‐BF2 and bis‐NSAID‐CUR hybrids exhibited low cytotoxicity in NCI‐60 assay, and in independent cell viability assay on colorectal cancer (CRC) cells (HCT116, HT29, DLD‐1, RKO, SW837, CaCo2) and in normal CR cells (CCD841CoN). By contrast, the mono‐naproxin and mono‐flurbiprofen CUR‐BF2 adducts exhibited remarkable anti‐proliferative and apoptopic activity in NCI‐60 assay most notably against HCT‐116 (colon), OVCAR‐3 (ovarian), and ACHN (renal) cells. Computational molecular docking calculations showed favorable binding energies to HER2, VEGFR2, BRAF, and Bcl‐2 as well as to COX‐1 and COX‐2, which in several cases exceeded known inhibitors. The main interactions between the ligands and the proteins were hydrophobic, although several hydrogen bonds were also observed. A sub‐set of six compounds that had exhibited little or no cytotoxicity were tested for their anti‐inflammatory response with THP‐1 human macrophages in comparison to parent NSAIDs or parent curcumin.

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Section: Resultsmentioning

confidence: 99%

“…By using a different strategy (Scheme ) a library of bis ‐NSAID/CUR and mono ‐NSAID/CUR conjugates were synthesized, from which the corresponding CUR‐BF 2 adducts were obtained by reaction with BF 3 …”

Section: Resultsmentioning

confidence: 99%

Curcumin Conjugates of Non‐steroidal Anti‐Inflammatory Drugs: Synthesis, Structures, Anti‐proliferative Assays, Computational Docking, and Inflammatory Response

et al. 2020

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“…The method developed by Liu et al [ 33 ] was applied to synthesize borodifluorinated curcumins and was subsequently accompanied by microwave hydrolysis developed by Abonia and co-workers [ 34 ] ( Figure 2 ). It is worth noting that microwave hydrolysis, in contrast to the Pabon method [ 35 ], offers much higher yields and a more straightforward purification procedure.…”

Section: Resultsmentioning

confidence: 99%

“…The aromatic aldehyde PEGylation (compounds 1 , 2 , and 3 ) was performed using the nucleophilic substitution method. The borodifluorinated derivatives (compounds 4 , 6 , 8 , 10 , and 12 ) were synthesized according to the method presented by Liu et al [ 33 ], and derivatives with unmodified diketo moiety (compounds 5 , 7 , 9 , 11 , and 13 ) were obtained by microwave hydrolysis developed by Abonia et al [ 34 ]. Abbreviations: DMF, dimethylformamide; MW, microwave.…”

Section: Figurementioning

confidence: 99%

Enhanced Cytotoxic Activity of PEGylated Curcumin Derivatives: Synthesis, Structure–Activity Evaluation, and Biological Activity

Łażewski

Kucińska

Potapskiy

et al. 2023

IJMS

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Curcumin has been modified in various ways to broaden its application in medicine and address its limitations. In this study, we present a series of curcumin-based derivatives obtained by replacing the hydroxy groups in the feruloyl moiety with polyethylene glycol (PEG) chains and the addition of the BF2 moiety to the carbonyl groups. Tested compounds were screened for their cytotoxic activity toward two bladder cancer cell lines, 5637 and SCaBER, and a noncancerous cell line derived from lung fibroblasts (MRC-5). Cell viability was analyzed under normoxic and hypoxic conditions (1% oxygen). Structure–activity relationships (SARs) are discussed, and curcumin derivatives equipped within feruloyl moieties with 3-methoxy and 4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy} substituents (5) were selected for further analysis. Compound 5 did not affect the viability of MRC-5 cells and exerted a stronger cytotoxic effect under hypoxic conditions. However, the flow cytometry studies showed that PEGylation did not improve cellular uptake. Another observation was that the lack of serum proteins limits the intracellular uptake of curcumin derivative 5. The preliminary mechanism of action studies indicated that compound 5 under hypoxic conditions induced G2/M arrest in a dose-dependent manner and increased the expression of stress-related proteins such as p21/CIP1, phosphorylated HSP27, ADAMTS-1, and phosphorylated JNK. In summary, the results of the studies indicated that PEGylated curcumin is a more potent compound against bladder cancer cell lines than the parent compound, and derivative 5 is worthy of further investigation to clarify its mechanism of anticancer action under hypoxic conditions.

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“…A more drastic substitution was performed, introducing electron withdrawing substituents into benzene rings, or even condensing heterocycles ( Table 3 ) [ 417 ].…”

Section: Curcumin and Curcuminoidsmentioning

confidence: 99%

Tailored Functionalization of Natural Phenols to Improve Biological Activity

et al. 2021

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Phenols are widespread in nature, being the major components of several plants and essential oils. Natural phenols’ anti-microbial, anti-bacterial, anti-oxidant, pharmacological and nutritional properties are, nowadays, well established. Hence, given their peculiar biological role, numerous studies are currently ongoing to overcome their limitations, as well as to enhance their activity. In this review, the functionalization of selected natural phenols is critically examined, mainly highlighting their improved bioactivity after the proper chemical transformations. In particular, functionalization of the most abundant naturally occurring monophenols, diphenols, lipidic phenols, phenolic acids, polyphenols and curcumin derivatives is explored.

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A Flexible Strategy for Modular Synthesis of Curcuminoid‐BF₂/Curcuminoid Pairs and Their Comparative Antiproliferative Activity in Human Cancer Cell Lines

Cited by 9 publications

References 30 publications

Curcumin Conjugates of Non‐steroidal Anti‐Inflammatory Drugs: Synthesis, Structures, Anti‐proliferative Assays, Computational Docking, and Inflammatory Response

Curcumin Conjugates of Non‐steroidal Anti‐Inflammatory Drugs: Synthesis, Structures, Anti‐proliferative Assays, Computational Docking, and Inflammatory Response

Enhanced Cytotoxic Activity of PEGylated Curcumin Derivatives: Synthesis, Structure–Activity Evaluation, and Biological Activity

Tailored Functionalization of Natural Phenols to Improve Biological Activity

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A Flexible Strategy for Modular Synthesis of Curcuminoid‐BF2/Curcuminoid Pairs and Their Comparative Antiproliferative Activity in Human Cancer Cell Lines

Cited by 9 publications

References 30 publications

Curcumin Conjugates of Non‐steroidal Anti‐Inflammatory Drugs: Synthesis, Structures, Anti‐proliferative Assays, Computational Docking, and Inflammatory Response

Curcumin Conjugates of Non‐steroidal Anti‐Inflammatory Drugs: Synthesis, Structures, Anti‐proliferative Assays, Computational Docking, and Inflammatory Response

Enhanced Cytotoxic Activity of PEGylated Curcumin Derivatives: Synthesis, Structure–Activity Evaluation, and Biological Activity

Tailored Functionalization of Natural Phenols to Improve Biological Activity

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Product

Resources

About

A Flexible Strategy for Modular Synthesis of Curcuminoid‐BF₂/Curcuminoid Pairs and Their Comparative Antiproliferative Activity in Human Cancer Cell Lines